An Antiparasitic Compound from the Medicines for Malaria Venture Pathogen Box Promotes Leishmania Tubulin Polymerization.
An Antiparasitic Compound from the Medicines for Malaria Venture Pathogen Box Promotes Leishmania Tubulin Polymerization.
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DOI：
10.1021/acsinfecdis.0c00122
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发表时间：
2020-08-14
影响因子：
5.3
通讯作者：
Wetzel DM
中科院分区：
文献类型：
--
作者：
Ullah I;Gahalawat S;Booshehri LM;Niederstrasser H;Majumdar S;Leija C;Bradford JM;Hu B;Ready JM;Wetzel DM
少数一线抗利什曼病药物疗效差且有毒。为了寻找治疗这种被忽视的热带疾病的新药，我们测试了疟疾风险药物（MMV）“病原体盒”中化合物对亚马逊利什曼原虫无鞭毛体的活性。筛选产生了6种发现的抗利什曼原虫化合物，其EC 50值为50至480 nM。浓度-反应测定表明，最佳命中MMV 676477对细胞内无鞭毛利什曼原虫、布氏锥虫和恶性疟原虫具有中等纳摩尔的杀细胞效力，表明具有广泛的抗寄生虫活性。我们在一小组MMV 676477类似物中探索了构效关系（SAR），并观察到对纯利什曼原虫无鞭毛体的较宽效价范围（20-5000 nM）。与MMV 676477相比，我们最有效的类似物SW 41的抗利什曼病效力提高了约5倍。多条证据表明MMV 676477选择性破坏利什曼原虫微管蛋白动力学。形态学研究表明，MMV 676477及其类似物影响L.细胞分裂过程中。差速离心显示MMV 676477促进寄生虫中细胞微管蛋白向聚合物形式的分配。使用纯化利什曼原虫和猪微管蛋白进行的湍流试验表明，MMV 676477以浓度依赖性方式促进利什曼原虫微管蛋白聚合。类似物的抗寄生虫活性与其促进纯化的利什曼原虫微管蛋白聚合的能力相关。化学交联证明MMV 676477支架与纯化的利什曼原虫微管蛋白结合，竞争研究建立了结合和抗利什曼原虫活性之间的相关性。我们的研究表明，MMV 676477是一种有效的抗寄生虫化合物，优先促进利什曼原虫微管聚合。由于其对多种寄生虫的选择性和广谱活性，这种支架显示出抗寄生虫药物开发的前景。
The few frontline antileishmanial drugs are poorly effective and toxic. To search for new drugs for this neglected tropical disease, we tested the activity of compounds in the Medicines for Malaria Venture (MMV) “Pathogen Box” against Leishmania amazonensis axenic amastigotes. Screening yielded six discovery antileishmanial compounds with EC50 values from 50 to 480 nM. Concentration–response assays demonstrated that the best hit, MMV676477, had mid-nanomolar cytocidal potency against intracellular Leishmania amastigotes, Trypanosoma brucei, and Plasmodium falciparum, suggesting broad antiparasitic activity. We explored structure–activity relationships (SAR) within a small group of MMV676477 analogs and observed a wide potency range (20–5000 nM) against axenic Leishmania amastigotes. Compared to MMV676477, our most potent analog, SW41, had ~5-fold improved antileishmanial potency. Multiple lines of evidence suggest that MMV676477 selectively disrupts Leishmania tubulin dynamics. Morphological studies indicated that MMV676477 and analogs affected L. amazonensis during cell division. Differential centrifugation showed that MMV676477 promoted partitioning of cellular tubulin toward the polymeric form in parasites. Turbidity assays with purified Leishmania and porcine tubulin demonstrated that MMV676477 promoted leishmanial tubulin polymerization in a concentration-dependent manner. Analogs’ antiparasitic activity correlated with their ability to facilitate purified Leishmania tubulin polymerization. Chemical cross-linking demonstrated binding of the MMV676477 scaffold to purified Leishmania tubulin, and competition studies established a correlation between binding and antileishmanial activity. Our studies demonstrate that MMV676477 is a potent antiparasitic compound that preferentially promotes Leishmania microtubule polymerization. Due to its selectivity for and broad-spectrum activity against multiple parasites, this scaffold shows promise for antiparasitic drug development.
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影响因子：
56.9
作者：
CHAN, MMY;FONG, D
通讯作者：
FONG, D
影响因子：
120.1
作者：
Katsuno, Kei;Burrows, Jeremy N.;Slingsby, B. T.
通讯作者：
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作者：
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作者：
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作者：
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